Synthesis of unsymmetrical N-(2-tert-butylphenyl)-N-(4-tert-butylphenyl)nitroxyl radical, the first stable diarylnitroxyl with vacant para-position

Article abstract of DOI:10.1016/j.mencom.2016.11.026

The title compound, first example of a stable diarylnitroxyl with vacant para-position, was best synthesized by CuCl-assisted coupling of o-tert-butylnitrosobenzene and p-tert-butylphenylboronic acid followed by N-xidation of the thus obtained unsymmetrical diarylamine. ESR investigation showed that ortho-substituted aromatic ring is removed from the conjugation plane providing unusual stability of this radical.

Full text of DOI:10.1016/j.mencom.2016.11.026

Mendeleev
Communications
Mendeleev Commun., 2016, 26, 535–537
Synthesis of unsymmetrical N-(2-tert-butylphenyl)-N-(4-tert-butylphenyl)-
nitroxyl radical, the first stable diarylnitroxyl with vacant para-position
Oleg A. Levitskiy, Vyacheslav V. Sentyurin, Alexey V. Bogdanov and Tatiana V. Magdesieva*
Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation.
Fax: +7 495 939 5536; e-mail: tvm@org.chem.msu.ru
DOI: 10.1016/j.mencom.2016.11.026
The title compound, first example of a stable diarylnitroxyl
with vacant para-position, was best synthesized by CuCl-
assisted coupling of o-tert-butylnitrosobenzene and p-tert-
butylphenylboronic acid followed by N-oxidation of the thus
obtained unsymmetrical diarylamine. ESR investigation
showed that ortho-substituted aromatic ring is removed
from the conjugation plane providing unusual stability of
this radical.
via
oxidative
amination
via
reductive
amination
New stable nitroxyl radical
N,N-Disubstituted aminoxyl radicals (so called, nitroxyls), stable
organic radicals with spin-density localization on the oxygen
atom, are widely used in various areas.1 The most studied dialkyl-
substituted radical is TEMPO (2,2,6,6-tetramethylpiperidine-
1-oxyl). Diarylnitroxides, contrary to their alkyl counterparts, are
much less investigated. The limited number of diarylnitroxides
available is attributed, first of all, to a lack of convenient synthetic
routes. Commonly, two synthetic approaches to diarylnitroxyls
are used, i.e., oxidation of diarylhydroxylamines or diarylamines.
Diarylamines are more available starting compounds than hydroxyl-
amines, therefore, the second approach seems preferable. Syn-
thesis of unsymmetrical diarylnitroxyls imposes additional limita-
tions on the scope of the reactions applicable to the preparation
of diarylamine precursors.
be efficient leading to unsymmetrical diarylamine 2 in practical
81% yield (Scheme 1).†
The opposite combination of the reactants 3b + 4a gives the
same unsymmetrical diarylamine 2 in much lower yield (27%,
Scheme 1).
N=O
R2
B(OH)2
R2
i
+
81% (3a + 4b)
27% (3b + 4a)
R1
R1
3a,b
4a,b
But
O
N
But
H
N
ii
Metal-catalyzed amination of aromatic substrates is a power-
ful tool for C(sp2)–N bond formation.2–5 Usually, catalysis is
most efficient when precious metals are used, commonly as
complexes with sophisticated phosphine ligands. Among other
compounds, synthesis of ortho-substituted aryl derivatives is
more difficult due to additional contribution of sterical demands.
Here, we report the synthesis of new stable unsymmetrical
N-(2-tert-butylphenyl)-N-(4-tert-butylphenyl) nitroxyl radical 1.
In all previously reported stable diarylnitroxyls6–13 both para-
positions in the aromatic rings were blocked by appropriate sub-
stituents to prevent possible radical coupling onto para-posi-
tion.14 The herein obtained unsymmetrical radical is the first
example of a stable diarylnitroxyl in which one of the phenyl rings
has a vacant para-position. New compound seems promising as
redox active electrode material.
In an effort to develop a practical precious metal-free method
for the synthesis of sterically hindered unsymmetrical N-(2-tert-
butylphenyl)-N-(4-tert-butylphenyl)amine 2 we explored the
copper catalyzed oxidative and reductive amination of o- and
p-tert-butylphenyl boronic acids. Among them, the most appro-
priate version is mild reductive amination of arylboronic acids
with nitrosoarenes15 mediated by CuCl which serves as a catalyst
and reducing agent. However, it has not been tested for sterically
demanding arylboronic acids and arylnitroso compounds. To
fill the void, the coupling of o-tert-butynitrosobenzene 3a and
p-tert-butylphenylboronic acid 4b was performed. It turned to
45%
But
But
2
1
a R1 = H, R2 = But
b R1 = But, R2 = H
Scheme 1 Reagents and conditions: i, CuCl (1 equiv.), DMF, 60°C; ii, H2O2,
Na2WO4, MeOH, D.
†
Mass spectra were measured with a high-resolution time-of-flight Bruker
maXis instrument using electrospray ionization (ESI-MS).20 Measure-
ments were performed in positive ion mode, interface capillary voltage
at 4.5 kV, effective scan range at m/z 100–1200, external calibration
(0.016 m sodium formate in MeCN–water 1:1 mixture or ESI-L Low
Concentration Tuning Mix, Agilent Technologies), direct syringe injec-
tion at flow rate of 3 ml min–1, nitrogen as dry gas at 4 dm3 min–1, inter-
face temperature 180°C. The spectra were processed using Bruker Data
Analysis 4.0 software package.
ESR spectra were recorded on a Bruker EMX-plus instrument for solu-
tions in toluene deaerated using standard freeze-pump-thaw technique
containing approximately 5×1015 radical molecules.
1H (400.0 MHz) and 13C (100.6 MHz) NMR spectra were recorded
using an Agilent 400-MR spectrometer in CDCl3. Chemical shifts were
referenced to residual protons.
N-(2-tert-butylphenyl)-N-(4-tert-butylphenyl)amine 2. Into an argon
filled two-neck flask fitted with reflux condenser and pressure-equalizing
dropping funnel and containing CuCl (79 mg, 0.80 mmol), a solution
of o-tert-butylnitrosobenzene 3a (130 mg, 0.80 mmol) in dry deaerated
DMF (20 ml) was added. The mixture was stirred at 60°C (water bath)
© 2016 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2016, 26, 535–537
NH2
But
(HO)2B
i
+
2
22%
But
5
4b
Scheme 2 Reagents and conditions: i, Cu(OAc)2, Et3N, CH2Cl2, ~20°C, 48 h.
As an alternative route, the oxidative amination16–19 of aryl-
boronic acid with anilines was also considered (Scheme 2).
In our case, o-tert-butylaniline 5 was reacted with p-tert-butyl-
phenylboronic acid 4b in the presence of equimolar amount
of Cu(OAc)2 in CH2Cl2 and Et3N, which afforded the unsym-
metrical amine 2 in 22% yield.‡ This result indicates that oxidative
amination is more sensitive to the presence of bulky substituents
in the reactants than reductive amination. Taking into account
that the location of a bulky group in arylboronic acid is less
beneficial than in the N-containing reactant, one can expect that
alternative combination (o-tert-butylphenylboronic acid 4a and
p-tert-butylaniline) should be unsuccessful.
3480
3490
3500
3510
3520
H/G
Figure 1 Experimental (black) and simulated (red) ESR spectra of N-(2-tert-
butylphenyl)-N-(4-tert-butylphenyl)nitroxyl in toluene. g = 2.0060, aN
= 10.43 G, aH,ortho = 2.65 G (2H), aH,meta = 0.88 G (2H); spin-coupling con-
stants for the second aromatic moiety: aH = 0.66 G (1H), aH = 0.50 G (1H),
aH = 0.43 G (1H); Hpp(Gauss) = 0.325 G, Hpp(Lorentz) = 0.198 G.
=
achieved using H2O2 in boiling methanol in the presence of
H2O2/Na2WO4 (45% yield of 1, see Scheme 1). The oxidation
with mCPBA in diethyl ether provided the targeted nitroxyl in
essentially lower yield (19%).§ This result is in line with the
previously reported data for symmetrical bis(p-tert-butylphenyl)-
nitroxyl.12
The new unsymmetrical N-(2-tert-bytylphenyl)-N-(4-tert-butyl-
phenyl)nitroxyl radical 1 obtained was characterized by ESI-
HRMS.§
ESR investigation of nitroxyl radical 1 gave an explanation
for unusual stability of the compound, in spite of the presence of
the vacant para-position in one of the aromatic rings. It turned
out that the ortho-substituted aromatic ring is removed from the
conjugation plane, which becomes evident from the characteristic
spin splitting (Figure 1) pattern. Splitting on two equivalent ortho-
protons and two equivalent meta-protons of only one aromatic
system is observed for asymmetrical radical. Almost undetectable
deviation of the shape of the observed signal from the perfect
triple of triplets of triplets indicates the presence of negligible
spin density on the second aromatic ring. Hence, the conjugation
of this aromatic system (containing o-tert-butyl group) with the
nitroxyl radical is almost absent thus preventing possible follow-up
radical transformations via vacant para-position.
In conclusion, the obtained results demonstrate that the rational
design of the structure of stable diarylnitroxyls can be based not
only on introducing substituents with appropriate electronic effects
in the aromatic rings but on changing the degree of conjugation
between nitroxyl group and aromatic moiety as well. The latter
sterical factor can be considered as an additional important
instrument for fine structural tuning.
For oxidation of N-(2-tert-butylphenyl)-N-(4-tert-butylphenyl)-
amine 2, several oxidants were tested. The best results were
for 30 min. Then the solution of p-tert-butylphenylboronic 4b (155 mg,
0.87 mmol) acid in dry deaerated DMF (7 ml) was added and the mixture
was stirred at 60°C for 16 h. The colour of the solution changed from
light green to black via light yellow, green and greenish blue. Afterwards
the mixture was diluted with water (100 ml) and saturated aqueous
ammonia (50 ml) and extracted with diethyl ether. The extracts were
dried with anhydrous sodium sulfate, evaporated and purified by column
chromatography on silica gel (eluent, toluene–hexane, 1:20). Three frac-
tions were collected (in order of elution): 4,4'-di-tert-butylbiphenyl (34 mg),
o-tert-butylnitrosobenzene (10 mg) and product 2 (183 mg, 81% yield).
1
For 2: white crystals, mp 86–88°C. H NMR (400 MHz, CDCl3) d:
7.40 (dd, 1H, o-H, J 7.9 and 1.5 Hz), 7.28 (dd, 1H, o-H, J 7.9 and 1.5 Hz),
7.25–7.21 (m, 2H, p-H), 7.14 (ddd, 1H, o-H, J 7.9, 7.3 and 1.6 Hz), 7.01
(ddd, 1H, o-H, J 7.9, 7.3 and 1.5 Hz), 6.83–6.79 (m, 2H, p-H), 5.37 (s,
1H, 7-NH), 1.45 (s, 9H, But), 1.31 (s, 9H, But). 13C NMR (101 MHz,
CDCl3) d: 142.99 (p-C), 142.59 (o-C), 142.09 (o-C), 142.05 (p-C),
127.04 (o-C), 126.93 (o-C), 126.18 (p-C), 124.47 (o-C), 123.07 (o-C),
116.65 (p-C), 34.90 (CMe3), 34.19 (CMe3), 31.68 (CMe3), 30.70 (CMe3).
ESI-HRMS, m/z: 228.2216 [M + H]+ (calc. for C20H28N, m/z: 282.2217).
‡
To a stirred solution of 560 mg of o-tert-butylaniline 5, 1.0 g of p-tert-
butylphenylboronic acid 4b and 1.6 ml of triethylamine in 12 ml of CH2Cl2,
1.36 g of anhydrous copper(ii) acetate was added. The slurry was stirred
under ambient conditions for 48 h and filtered; the filtrate was evaporated
and the residue was purified by column chromatography on silica gel
(toluene–hexane, 1:20). The unsymmetrical amine 2 was obtained as
white crystals in 22% yield (220 mg).
§
N-(2-tert-bytylphenyl)-N-(4-tert-butylphenyl)nitroxyl 1.
Method 1. A solution of diarylamine 2 (281 mg, 1.0 mmol) in 5 ml of
methanol was heated to the boiling point, then 30% hydrogen peroxide
(340 ml, 3.0 mmol) and a solution of Na2WO4∙2H2O (33 mg, 0.1 mmol)
in water (70 ml) were successively added and the mixture was refluxed for
12 h. New portions of hydrogen peroxide (340 ml) were added every 3 h.
The consumption of diarylamine was monitored by TLC (eluent, toluene–
hexane, 1:10). After all the starting material was consumed, the mixture
was cooled, diluted with water and extracted with diethyl ether. The organic
fractions were washed with water, dried over sodium sulfate and purified
by column chromatography on silica gel (eluent, toluene; Rf 0.44). Nitroxyl
was obtained as an orange-red oil (133 mg, 45% yield). ESI-HRMS, m/z:
296.2012 [M]+ (calc. for C20H26NO, m/z: 296.2009), 297.2078 [M + H]+
(calc. for C20H27NO, m/z: 297.2087).
Method 2. A solution of mCPBA (46 mg, 0.29 mmol) in diethyl ether
(1 ml) was added to a solution of diarylamine 2 (50 mg, 0.18 mmol) in
diethyl ether (1.5 ml) cooled to –15°C. The mixture was kept at –15°C
for 10 min and, afterwards, at room temperature for 2 h. The colour of
the solution gradually changed to dark red. The mixture was quenched
with water, washed with saturated aqueous NaHCO3, dried over Na2SO4,
evaporated and purified by column chromatography on silica gel (eluent,
toluene); 10 mg (19%) of the nitroxyl was obtained.
This work was supported by the Russian Science Foundation
(project no. 16-13-10282). NMR parts of this work were supported
by the M. V. Lomonosov Moscow State University ‘Program of
Development’. We are grateful to D. Eremin for MS analysis;
mass spectra were recorded in Department of Structural Studies,
N. D. Zelinsky Institute of Organic Chemistry RAS.
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